The present invention relates to soft gelatin capsules having a capsule shell made of gelatin, plasticizing agents, in particular 1,2-propylene glycol, and optionally further auxiliary materials, and a capsule filling containing solvent, adjuvants and one or more pharmacologically active substances. The invention further relates to a process for preparing such soft gelatin capsules.
Some pharmacologically active substances may have biopharmaceutical and/or physicochemical properties which make them difficult to formulate into commercially acceptable formulations. Such substances may however be conveniently administered in liquid form, e.g. in a complex carrier medium made up of several components. Solvents such as 1,2-propylene glycol and dimethyl isosorbide have great potential in such carrier media. The carrier medium may be designed to form an emulsion in the stomach thereby facilitating absorption of the pharmacologically active substance. The carrier medium may have to be accurately prepared and even slight variations in the composition cannot be tolerated without irreversibly upsetting the system, and destroying its beneficial properties. Thus the solubilizing properties of the capsule filling may be changed and the active substance precipitates out. This precipitation process may be irreversible, and the patient is under-dosed. The emulsifying properties of the capsule filling may be changed, and, upon administration, an emulsion may not be formed in the stomach and the pharmacologically active substance is not correctly or reproducibly absorbed.
Encapsulation of such liquid formulations in soft gelatine capsules potentially offers a very convenient way of administering such pharmacologically active substances. However the manufacture of commercially acceptable liquid filled soft gelatine capsules is fraught with difficulties which restricts the availability of this approach. Thus, during manufacture, the capsule shell is formed from wet gelatine bands and the resultant wet capsules are dried. During this stage or even afterwards, we have found that components in the capsule filling may migrate into the capsule shell, and vice versa, thereby changing the composition of the capsule filling at least in the boundary region near the interface of the capsule filling and the capsule shell, with the result that the beneficial properties of the capsule filling are lost.
In recent years microemulsion pre-concentrates have been developed as carrier media for active substances which are sparingly soluble in water, which microemulsion pre-concentrates exhibit a distinct improvement in the bioavailability. Examples of such microemulsion pre-concentrates have been described, for example, in the UK patent application No 2 222 770 A (equivalent to DE-A-39 30 928) for the active substance cyclosporin. Microemulsion pre-concentrates consist of a hydrophilic phase, a lipophilic phase and a surface-active agent. As the hydrophilic phase there has been expressly mentioned and also used in the examples propyleneglycol, and more specifically 1,2-propylene-glycol. UK patent application No 2 222 770 A mentions, as an application form of the microemulsion pre-concentrates in addition to hard gelatin capsules, also soft gelatin capsules as well as other parenteral or topically applicable forms; cf. page 13, lines 16-25. We have found that microemulsion pre-concentrates comprising 1,2-propyleneglycol as the hydrophilic phase in soft gelatin capsules are prone to the migration of the 1,2-propyleneglycol into the capsule shell from the capsule filling. Not only softening of the capsule shell occurred, but also a destruction of the microemulsion pre-concentrates, because the hydrophilic component was withdrawn therefrom.
Since propyleneglycol, and more specifically 1,2-propyleneglycol, is a good hydrophilic solvent, it would be desirable to employ this solvent also for the preparation of capsule fillings. It is true, it is readily possible to produce such gelatin capsules wherein, for example, glycerol or sorbitol are used as the plasticizer for the capsule shell. However, such soft gelatin capsules are not stable, since with the lapse of time the propyleneglycol migrates into the capsule shell from the capsule filling so that the capsules will become weak.
Furthermore, such softened capsules will undergo deformation, because due to the migration of part of the solvent into the capsule shell from the capsule filling there will be a decrease in volume and a reduction in pressure in the interior of the capsule.
We have now found that the migration of, e.g. 1,2-propyleneglycol, may be hindered by using this component in the gelatine band composition with the result that it is present in the capsule shell. However we also experienced difficulties in the commercial manufacture of soft gelatine capsules containing 1,2,propylene glycol.
In EP-B-0 121 321 there have been disclosed soft gelatin capsules wherein at least one pharmacologically active substance has been dissolved or suspended in a liquid polyethyleneglycol, the capsule comprising gelatin, a plasticizer therefor and a compound for preventing embrittlement which compound is a mixture comprising sorbitol and at least one sorbitan. If so desired, alcohols having several hydroxyl groups are added to the capsule shell as the embrittlement-preventing compound. As polyhydric alcohols suitable for this purpose there have been mentioned glycerol, sorbitol and propyleneglycol. Furthermore this patent specification mentions that the capsule filling may also contain such alcohols comprising several hydroxyl groups. Again glycerol, sorbitol and propyleneglycol have been described. However, it is conspicuous that in the examples glycerol has been exclusively used for the capsule filling as well as for the capsule shell. This may be to the fact that the attempts to substitute propyleneglycol for glycerol in the capsule shell failed. Although propyleneglycol is basically suitable as a plasticizer for gelatin, in the large scale commercial manufacture of such soft gelatin capsules according to the so-called Rotary Die Process the gelatin bands, once poured onto the cooling drums, may be removed only with difficulty from the cooling drums and passed to the molding rolls where the encapsulation is effected. The reason therefor is that the gelatin bands containing propyleneglycol as the plasticizer are substantially more tacky than those containing glycerol or sorbitol as the plasticizer. This is why soft gelatin capsules having a capsule shell comprising gelatin and propyleneglycol as a plasticizer have never been introduced into practice.
In EP-B-0 257 386 there have been disclosed gelatin capsules which, in the capsule filling, contain a solvent mixture which contains at least 5% by weight of ethanol and at least 20% by weight of one or more partial glycerides of fatty acids having from 6 to 18 carbon atoms. In the description there has been mentioned that the capsule shell may contain glycerol, propyleneglycol, sorbitol and sorbitans as the plasticizer. However, again just glycerol, sorbitol and sorbitans were used in the capsule shell, because propylene glycol results in the above-described undesirable tackiness.
Since the use as a plasticizer of propyleneglycol in the capsule shell results in difficulties in the manufacture of soft gelatin capsules according to the Rotary Die Process, there was a further need for developing a process wherein the manufacture of soft gelatin capsules according to the Rotary Die Process is possible even in the case where the capsule shell contains a component which leads to tackiness, e.g. 1,2-propyleneglycol.
We have found surprisingly by cooling the cooling drum with a liquid coolant it is possible to eliminatexe2x80x94or at least to suppressxe2x80x94the troublesome tackiness observed, and a commercially feasible manufacture of such soft gelatin capsules is possible.
Therefore, the present invention provides soft gelatin capsules which include a capsule shell comprising gelatin, plasticizers and, if desired or required, further auxiliary materials, and a capsule filling containing solvent, adjuvants and one or more pharmacologically active substance(s), wherein the solvent of the capsule filling, at least in part, is a migrateable component and which, nevertheless, are stable.
Using the process according to the invention it is also possible to produce soft gelatin capsules according to EP-B-0 121 321 which contain liquid polyethyleneglycol in the capsule filling and 1,2-propyleneglycol in the shell.
In one aspect the invention provides a liquid filled soft gelatin capsule characterized in that the capsule shell contains a migrateable component (other than glycerol) which is also present in the capsule filling.
In another aspect the present invention provides a process for encapsulating a liquid mixture in gelatine to form soft gelatine capsules, wherein one component of the mixture has a propensity to migrate into gelatine, characterized in that the gelatine composition used in the encapsulation process contains also the said migrateable component, and said migrateable component is other than glycerol.
In another aspect the present invention provides a process for manufacturing soft gelatin capsules having a capsule shell comprising gelatin and a component which leads to tackiness, characterized in that cooling of the gelatin bands to form the capsule shell is effected using a liquid coolant. Preferably, but not necessarily, the component which leads to tackiness is a migrateable component.
Typical migrateable components include non-volatile pharmaceutically acceptable solvents which are capable of mixing with, or forming a solid solution with, the gelatine. As mentioned above glycerol is mentioned in the above EP-B-0-121321. However, glycerol is not a particularly good solvent, and in general does not lead to tackiness. Glycerol may of course also be present as described hereinafter.
Typical migrateable solvents include tetrahyrofurylalcohol ethers, e.g. glycofurol diethylene glycol mono ethyl ether, e.g. transcutol, 1,3-dimethyl-2-imidazolidinone, dimethylisosorbide, polyethylene glycol (e.g. of molecular weight from 200 to 600) and preferably propylene glycol or solvents having similar migration capability. Preferably, the concentration of the migrateable component in the capsule shell is chosen to be so high that an approximately stable equilibrium of the concentrations between the capsule shell and the capsule filling is established soon after encapsulation. During the equilibration phase the migrateable component may migrate from the capsule shell into the capsule filling (thereby increasing its concentration in the capsule filling and decreasing it in the gelatine shell), but migration of the migrateable component into the capsule shell from the capsule filling is significantly reduced.
In one embodiment of the invention the carrier filling at least partially is 1,2-propyleneglycol, but not predominantly polyethyleneglycol. In another aspect the present invention accordingly provides a soft gelatin capsule having a capsule shell comprising gelatin, plasticizers and, if desired or required, further auxiliary agents, and a capsule filling containing a solvent, wherein the solvent at least partially is 1,2-propyleneglycol, but not predominantly polyethyleneglycol, characterized in that the capsule shell contains 1,2-propyleneglycol.
The term gelatin as used herein includes not only unmodified gelatin as in the European Pharmacopeia and NF but also modified gelatin such as succinated gelatin.
Typical pharmacologically active substances include substances difficultly soluble in water, which have a solubility in water of less than 1% (w/v) such as cyclosporins and macrolides. Cyclosporins comprise a class of structurally distinct, cyclic, poly-N-methylated undecapeptides, generally possessing immunosuppressive, anti-inflammatory, anti-viral multidrug resistant and/or anti-parasitic activity, each to a greater or lesser degree. The first of the cyclosporins to be identified was the fungal metabolite Cyclosporin A, or Ciclosporin, and its structure is given in The Merck Index, 11th Edition; Merck and Co., Inc.; Rahway, N.J. USA (1989) under listing 2759. Large numbers of other cyclosporins are also known and examples are disclosed in UK patent application No 2 222 770 A. These include e.g. natural cyclosporins e.g. cycloporin A or G or synthetic cyclosporin derivatives thereof, e.g. ([3xe2x80x2-desoxy-3xe2x80x2-oxo-MeBmt]1-[Val]2-Ciclosporin) or [0-(2-hydroxyethyl)-(D)Ser]8-Ciclosporin. Alternatively the pharmacologically active substance may be a macrolide such as a rapamycin, including derivatives thereof. Large numbers of derivatives of rapamycin have been synthesized, including for example those disclosed in U.S. Pat. Nos. 5,221,670 and 5,221,740, certain acyl and aminoacyl-rapamycins (see for example U.S. Pat. Nos. 4,316,885, 4,650,803, 5,151,413), and carbonates and amide esters (see for example EP 509795 and 515140) 27-desmethyl-rapamycin (see for example WO 92/14737), 26-dihydro-rapamycin (see for example U.S. Pat. No. 5,138,051), alkoxyester derivatives (see for example U.S. Pat. No. 5,233,036), and certain pyrazole derivatives (U.S. Pat. No. 5,164,399). A preferred rapamycin is 40-0-(2-hydroxy)ethyl rapamycin as disclosed in PCT/EP/93/02604.
FK 506 is a macrolide immunosuppressant that is produced by Streptomyces tsukubaensis No 9993. The structure of FK506 is given in the appendix to the Merck Index, as item A5. Also a large number of related compounds which retrain the basic structure and immunological properties of FK506 are also known. These compounds are described in a large number of publications, for example EP 184162, EP 315973, EP 323042, EP 423714, EP 427680, EP 465426, EP 474126, WO 91/13889, WO 91/19495, EP 484936, EP 532088, EP 532089, WO 93/5059 and the like. These compounds are termed collectively xe2x80x9cFK506 compoundsxe2x80x9d in this specification. Examples of compounds are FK 506, ascomycin and those disclosed in EP 427 680, e.g. Example 66a. Other preferred compounds are disclosed in EP 465 426.
Any of the pharmacologically active substances mentioned in the specifications referred to above may be used in the capsules of the invention, e.g. in the examples mentioned hereinafter.
The carrier medium may contain a wide variety of components besides the migrateable component, e.g. as described hereinafter. It may, for example, contain a component which is volatile to some extent at the temperature of capsule production or storage such as ethanol which will to a certain extent pass through the capsule shell until equilibrium is reached.
The present invention is of particular importance for the manufacture of soft gelatin capsules in which the capsule filling may form an emulsion on mixing with water, see e.g. WO 94/5312. Thus the capsule filling may be a microemulsion pre-concentrate containing e.g. 1,2-propyleneglycol as the hydrophilic component e.g. those disclosed in UK patent application Nos 2 222 770 A and 2 257 359 A.
Other components may include a hydrophilic component, lipophilic component, surfactants and co-surfactants mixed together to provide a uniform mixture.
The capsule filling may contain a mixture of C12-20 fatty acid mono-, di- and/or tri-glycerides e.g. from corn oil. Preferably the mono-, di-, and tri-glycerides have a low saturated fatty acid content preferably obtained from commercially available glycerol transesterification products by separation techniques as known in the art (for example purification to remove glycerol by washing and freezing procedures coupled with separation techniques such as centrifugation) to remove the saturated fatty acid components and enhance the unsaturated fatty acid component content. Typically the total saturated fatty acid component content will be less than 15%, (for example  less than 10%, or  less than 5%) by weight based on the total weight of the component. A reduction of the content of saturated fatty acid component in the mono-glyceride fraction may be observed after being subjected to the separation technique. A suitable process is described in WO 93/09211.
Because the undesirable migration into the capsule shell from the capsule filling is reduced, the amount of migrateable component to be used in the capsule shell depends on the desired initial and final concentrations of the migrateable component in the capsule filling. Thus, the content of migrateable component may be chosen so that the resulting concentration of migrateable component in the capsule shell after drying is from 2, e.g. 5, to 40% by weight. This may be accomplished by adding from 1 to 35% by weight of migrateable solvent to the gelatin composition. The gelatin composition initially contains water which in turn is removed in the subsequent drying operation.
A typical weight ratio of the migrateable component to gelatin is from 1:1 to 1:4.
The preferred range of the migrateable component content in the dried capsule shell is between 10 and 32%. In order to accomplish this, from 4 to 30% of migrateable component is added to the aqueous gelatin composition. Especially good results with microemulsion pre-concentrates containing 1,2-propyleneglycol as the hydrophilic component are achieved upon adding an amount of from 8 to 25% of migrateable component to the aqueous gelatin composition.
Another surprising advantage of the invention is that by using a migrateable component such as 1,2-propyleneglycol as the plasticizer in the capsule shell the amount of water required for dissolving and melting the gelatin may be reduced. While glycerol is highly viscous or syrupy and sorbitol itself even is a solid, the migrateable component such as 1,2-propyleneglycol may be a low-viscosity liquid. The reduction in the water content of the gelatin solution for producing the gelatin shell is a major advantage in that, during the process of drying the wet capsules, a smaller amount of water will make its way into the capsule filling from the initially moist shell. Thereby, with medicaments that are sparingly soluble in water, in many cases precipitation by crystallization of the active substance in the capsule filling can be prevented. Furthermore, due to the low diffusion of water into the capsule filling from the capsule shell a more stable capsule is obtained.
The capsule shell may of course additionally contain, as plasticizer in addition to the migrateable component, certain amounts of glycerol as well as conventional additives such as dyes, colorant pigments, flavoring agents, sugar, oligo-saccharides or polysaccharides. However, it is preferred that the capsule shell in the wet state and, thus, at the time of encapsulation, contains sufficient migrateable component so that any migration of the migrateable component into the capsule shell from the capsule filling is reduced or prevented. The equilibrium concentration in the first place is determined by the concentration in the capsule filling of migrateable component such as propyleneglycol. However, it may also be affected by the qualitative and quantitative composition of the lipophilic component, the surfactants and the co-surfactants as well as the amount of further components of the capsule filling and the capsule shell. Thus, the optimum amount of migrateable component in the aqueous gelatin composition for an intended capsule filling can be determined by way of some simple and conventional preliminary tests.
If glycerol is employed as a further plasticizer in the capsule shell in combination with migrateable component, the concentration of the glycerol may be less than 18%, and preferably even below 12%, relative to the weight of the moist capsule shell. A typical weight ratio of the migrateable component to glycerol is from 1:1 to 1:0.2.
The process according to the invention is basically carried out in the same manner as usual in accordance with the Rotary Die Process as described in greater detail, inter alia, in Lachmann et al., xe2x80x9cThe Theory and Practice of Industrial Pharmacyxe2x80x9d, 2nd Edition, pages 404-419. It is apparent from FIG. 13-9 and its description in page 414, right column, last paragraph, that the gelatin band is passed over an air-dried rotating drum. The temperature of the cold air was reported to be 56xc2x0 F. to 58xc2x0 F., corresponding to 13.3xc2x0 C. to 14.4xc2x0 C., but this only inefficiently cools the gelatine.